Tumor protein 53 (P53) is a tumor suppressing protein that regulates the cell cycle, suppresses tumors, and thereby prevents cancer. Murine double minute 2 (MDM2) is an important negative regulator of p53 and inhibitor of p53 transcriptional activation (see Vassilev 2006 Trends in Molecular Medicine 13(1), 23-31). MDM2 binds and inactivates p53 by directly blocking the p53 transactication domain and by serving as an E3 ubiquitin ligase for p53, thereby targeting p53 protein for ubiquitin-dependent degradation in the proteasome. About 11 million cancer patients have an inactivating mutation in the p53 protein.
EGFR is involved in the same cellular signaling pathway as MDM2. EGFR is a known cancer-associated molecule and EGFR inhibitors, such as Tarceva, provide targeted cancer treatment. Significant numbers of cancer patients become resistant to treatment with approved EGFR inhibitors, such as Tarceva. There is currently no approach to overcome such resistance.